The work done in this project has been an integral part of a team effort with NCI laboratories to develop new inhibitors of HIV that target the highly conserved nucleocapsid protein (NCp7). This Section has the responsibility to design the actual drug candidates and to direct and participate in their synthesis. As reported last year, we began exploring a number of variants of dithiobis(benzamides), a class of compounds previously shown by our group and others to selectively inactivate NCp7 through covalent modification of its zinc finger cysteines. In the course of this work, we synthesized other chemotypes and discovered that certain thiolesters (thioesters) showed considerable promise as antiviral agents as tested by in vitro assays for zinc ejection from recombinant NCp7, HIV antiviral potency (XTT test), and cellular toxicity. Some of these compounds, because of their low toxicity, exhibited very good therapeutic indices (low toxicity coupled with good potency). We have synthesized and screened a panel of the thiolesters, exploring various aspects of structure in relation to function. In particular, we identified a subclass of thiolesters that bear a pyridinium cationic group. These compounds which we dub, ?PATEs? (for pyridinioalkanoyl thiolesters), are noteworthy for their good potency (low micromolar EC50s), very low toxicity, and appreciable water solubility. Their low molecular weight and stability toward glutathione highlight potential advantages over the dithiobis(benzamides) and derivative benzisothiazolones, especially in regard to bioavailability and retention of in vivo activity. A paper covering the above research was published recently in the Journal of Medicinal Chemistry, following filing of a provisional US patent with the PTO. The patent covers the thiolester chemotype and its various possible applications, for treatment of HIV infection and for preparing diagnostic products and inactivated virus vaccines. - HIV inhibitors, antiviral agents, nucleocapsid, 2,2?-dithiobis(benzamides), zinc fingers, Benzisothiazolones, drug resistance